Heart failure and muscular dystrophies are two prominent diseases afflicting a large human population worldwide. The long-term goal of this proposal is to develop simple, safe and efficient strategies for gene transfer into both cardiac and skeletal muscles to achieve widespread and sustained transgene expression, which remains a challenging task particularly for systemic vector delivery through blood circulation. The immediate goal is to test the gene delivery and therapeutic strategies in a delta -sarcoglycan (delta -SG) deficient Syrian hamster model, a well-established congestive heart failure and muscular dystrophy animal model. In both humans and animals, a subset of limbgirdle muscular dystrophies (LGMD) caused by mutations in the sarcoglycan genes manifest both cardiomyopathy (CM) and muscular dystrophy. Recent advancement in AAV vectors has equipped us with a promising gene delivery vehicle. Gene therapy may now present a good opportunity for the development of novel therapeutics for LGMD in particular, and cardiomyopathy and muscular dystrophies in general. We have four specific aims in this proposal: 1) to identify the most efficient AAV serotype vectors for blood vessel-mediated cardiac and muscle gene transfer; 2) to study the gene therapy efficacy of congestive heart failure; 3) to study the gene therapy efficacy of sarcoglycan deficiency after intravascular and systemic delivery of the delta -sarcoglycan gene; 4) to improve heart-specific and muscle-specific transduction by a combination of targeted vector delivery and tissue-specific promoters.